BIODISTRIBUTION OF I-125 TYRAMINE TRANSFORMING GROWTH-FACTOR-ALPHA ANTISENSE OLIGONUCLEOTIDE IN ATHYMIC MICE WITH A HUMAN MAMMARY-TUMOR XENOGRAFT FOLLOWING INTRATUMORAL INJECTION

The Watson-Crick base pairing rule provides the underlying principle f or the antisense (AS) approach to inhibiting gene expression. Transfor ming growth factor alpha (TGF alpha) was the first growth factor to be associated with tumorigenesis, thus making the TGF alpha (mRNA) a pot ential target for AS therapy and offering the potential for monitoring of the progression of malignancy by non-invasive imaging with radiola belled AS phosphodiester, Probe labelling and biodistribution were stu died in the present report. A 23-mer oligonucleotide sequence was synt hesized and grafted in 5' with a tyramine group which was further radi oiodinated. The radiolabelled AS was injected intratumorally in mammar y tumour-bearing BALB/c mice (3 weeks after inoculation of 7 . 10(6) N S2T2A mammary cells). Biodistribution was monitored by sequential scin tigraphy and organ radioactivity after autopsy. The 5' tyramine group allowed specific and stable radiolabelling of the AS with I-125. The I -125 AS oligonucleotide was rapidly cleared from the tumour by intesti ne and kidneys. Four hours after intratumoral injection, 6.5%+/-1.5% o f the dose was retained in the tumour as non-degraded I-125 AS. It is concluded that 5' tyraminylated AS provides information on the biodist ribution of AS oligonucleotide following intratumoral injection. These data will contribute to the pharmacology of AS oligonucleotides which can be used for therapy.